OVERALL PROJECT SUMMARY The overarching goal of this PPG is to understand the role of the kidney in the pathogenesis of hypertension, a major cause of global mortality and a primary modifiable risk factor for renal, cardiovascular and cerebrovascular disease. Approximately half of all hypertensive subjects demonstrate sodium-sensitivity of blood pressure, the mechanisms of which are poorly understood. Several important discoveries from the investigators of this program provide unique conceptual insight into the development of salt-sensitive hypertension and renal damage and form the basis for this proposal. The integrated hypothesis of our program is that salt-induced hypertension proceeds in two phases. An initial, or primary, increase in blood pressure (BP) is followed by a more dramatic, secondary rise of BP that is dependent upon the initial increase in renal perfusion pressure (RPP) and culminates in `malignant hypertension' and renal end-organ damage. This global hypothesis will be tested in three projects which are exploring previously unrecognized areas of importance in hypertension. One entirely new area of research, to be examined in Project 1, is focused around the mechanisms of action of mTOR pathways in salt- sensitive hypertension and the potential therapeutic use of mTOR inhibition as a novel therapeutic strategy to treat hypertension. Project 2 is testing the innovative hypothesis that alterations in cellular metabolism, specifically insufficiencies in fumarase-related metabolism in the kidney, contribute to hypertension by decreasing arginine regeneration and nitric oxide levels. Project 3 is based upon the unique observation made in the current PPG indicating that an initial elevation in renal perfusion pressure is necessary to mediate the infiltration of immune cells into the kidney which amplifies the disease process; the proposed experiments will elucidate the molecular transduction of this physical force. To facilitate this important work, the projects are supported by an administrative core (Core A), and two scientific cores, which have been specially designed to meet the needs of the program and facilitate an economy of resources. Core B will supply the unique genetic animal models which have been generated to address the particular hypotheses of the scientific projects. Core C will provide many of the unique scientific approaches that will be used in the projects. Together, the three integrated projects and three cores of this PPG will provide important new information and insight into the mechanisms of salt-sensitive hypertension in a collaborative research effort that will accelerate the acquisition of knowledge more effectively than a simple aggregate of research projects that have no interaction or thematic integration.